Jan 2026· Human Mutation· Vol 2026· 0 citations· 53 references
Medicine
TL;DR
Findings confirm ARL2BP as a causative gene for both PCD and MMAF, expanding the genotypic and phenotypic spectrum of ciliopathies and recommending long‐term ophthalmological follow‐up to detect delayed‐onset retinal degeneration.
Abstract
Primary ciliary dyskinesia (PCD) and multiple morphological abnormalities of the sperm flagella (MMAF) frequently co‐occur in male infertility. However, the genetic basis of this syndromic presentation remains unclear. Using whole‐exome sequencing, we identified a novel homozygous ARL2BP splice‐site mutation (c.294‐2A>G) in a 23‐year‐old infertile male from a consanguineous family who presented with syndromic PCD and MMAF. This variant causes aberrant pre‐mRNA splicing and triggers nonsense‐mediated mRNA decay, resulting in the complete absence of ARL2BP protein expression. Transmission electron microscopy revealed extensive disorganization of flagellar axonemes with consistent central pair (CP) microtubule depletion and disorganization of peripheral doublets. Immunofluorescence confirmed a severe deficiency of the CP protein SPAG6 in the sperm flagella. Notably, the patient presented without retinal symptoms. Given that ARL2BP‐related retinitis pigmentosa generally emerges during the third decade, long‐term ophthalmological follow‐up is essential to detect delayed‐onset retinal degeneration. In conclusion, these findings confirm ARL2BP as a causative gene for both PCD and MMAF, expanding the genotypic and phenotypic spectrum of ciliopathies.
Findings identify LRGUK as a novel gene involved in male infertility, essential for spermatid morphogenesis and flagellum assembly, essential for spermatid morphogenesis and flagellum assembly.
Wiâme Mokkedem, Zeinab Wehbe, A. Barbotin et al.· Clinical Genetics· 0 citations
A novel domain-specific CFAP65 mutation associated with MMAF and male infertility in a consanguineous Pakistani family is identified, thereby expanding the known genetic mutational landscape of MMAF.
Musavir Abbas, Ansar Hussain, Ma Hui et al.· Basic and Clinical Andrology· 0 citations
Plasma proteomic analysis of patients with CILD40 identified significant enrichment of pathways related to platelet activation, complement and coagulation cascades and differential signatures in CILD40, highlighting the potential of plasma proteomics for understanding distinct pathogenic mechanisms across PCD subtypes.
Siming Kong, Mingshuo Wang, Xuedong Wang et al.· Phenomics· 0 citations
ABSTRACT Primary ciliary dyskinesia (PCD) is a clinical syndrome that in dogs primarily manifests as chronic respiratory disease associated with cilial malfunction. The current study employs whole‐genome sequencing and a candidate gene approach to uncover the genetic basis of PCD in three Cocker Spaniel siblings following diagnosis of their respiratory cilia by scanning electron microscopy and high‐speed video microscopy. Absence of the disorder in the parents suggested autosomal recessive inheritance. A 29 bp frameshift insertion in the eleventh exon of the candidate gene sperm‐associated antigen 1 (SPAG1) [NC_049234.1:g.2213788_2213789insGGCGGCGGCAAGCGGCCGGAGAGGGGCGC] was identified as likely causative for PCD in this family. The 29 bp frameshift variant was unobserved in a public variant call file including 1987 dogs from the Dog10K resource however an in‐frame insertion was sometimes observed at the same locus. A Cocker Spaniel with similar symptoms from a different family tested negative for the identified variant suggesting that there are multiple causes for the condition in Cocker Spaniels.
S. E. Mead, L. Hambrook, R. Suryadinata et al.· Animal Genetics· 0 citations
Acephalic spermatozoa syndrome (ASS) is a rare cause of male infertility characterized by sperm tails lacking heads. Although zinc finger MYND-type containing 15 (ZMYND15) mutations are linked to male infertility, their role in ASS is unknown. In this study, whole-exome sequencing identified novel homozygous truncating mutations, c.292C>T (p.Arg98Ter) and c.337G>T (p.Glu113Ter), in ZMYND15 from two infertile patients. These mutations caused protein truncation and impaired function, leading to extremely low sperm counts, poor motility, and numerous acephalic spermatozoa. Electron microscopy and sperm immunofluorescence revealed abnormal sperm neck structures, missing mitochondrial sheaths, failure of acrosome formation, and a lack of central microtubules. Experiments showed reduced mutant protein expression and high rates of degradation. Coimmunoprecipitation experiments indicated a direct interaction between ZMYND15 and Sad1 and UNC84 domain containing 5 (SUN5), crucial for forming the sperm head-tail connection. One patient achieved a live birth via intracytoplasmic sperm injection (ICSI), whereas the other had an early miscarriage. This study links ZMYND15 mutations directly to ASS, highlighting its role in spermatogenesis and offering insights for clinical diagnosis and treatment.
Qian-Jun Zhang, Hao Lin, Rui-Long Hao et al.· Asian Journal of Andrology· 0 citations
This study identifies novel loss-of-function RSPH4A variants causing PCD through distinct molecular mechanisms, expanding the mutational spectrum of radial spoke head protein-related ciliopathies.
Yuting Lu, Hui-Yan Tang, Kai Chen et al.· Frontiers in Genetics· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
